Korkola James E, Houldsworth Jane, Chadalavada Rajendrakumar S V, Olshen Adam B, Dobrzynski Debbie, Reuter Victor E, Bosl George J, Chaganti R S K
Cell Biology Program and Departments of Medicine, Epidemiology and Biostatistics, and Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Cancer Res. 2006 Jan 15;66(2):820-7. doi: 10.1158/0008-5472.CAN-05-2445.
Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray ( approximately 83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell-associated genes in embryonal carcinoma, including several core "stemness" genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas.
成年男性生殖细胞肿瘤（GCTs）包括不同的类型：精原细胞瘤和非精原细胞瘤，后者包括多能性胚胎癌以及表现出不同分化阶段的其他组织学亚型。几乎所有的GCTs都显示12号染色体短臂（12p）增加，但相关的靶基因尚未明确界定。为了鉴定12p靶基因，我们检测了17例精原细胞瘤、84例非精原细胞瘤GCTs以及5例正常睾丸样本的Affymetrix（加利福尼亚州圣克拉拉）U133A + B基因芯片（覆盖约83%的12p基因）表达谱。12p上的73个基因显著过表达，包括GLUT3和REA（在所有GCTs中均过表达）以及CCND2和FLJ22028（在除绒毛膜癌外的所有GCTs中过表达）。我们对12p13.31处一个200 kb的基因簇进行了特征分析，该基因簇在胚胎癌和精原细胞瘤中呈现协同过表达，其中包括已知的干细胞基因NANOG、STELLA和GDF3以及两个此前未鉴定的基因。对其他协同调控的干细胞基因基因组簇的搜索未发现与12p13.�1处类似的基因组区域。胚胎癌与精原细胞瘤的比较显示，胚胎癌中几个与干细胞相关的基因相对过表达，包括几个核心的“干性”基因（EBAF、TDGF1和SOX2）以及WNT、NODAL和FGF信号通路的几个下游靶点（FGF4、NODAL和ZFP42）。我们的结果表明，12p增加是一种功能相关的改变，通过激活关键的干细胞基因导致增殖激活以及干细胞功能的重新建立/维持。此外，核心干细胞基因的差异表达可能解释了胚胎癌和精原细胞瘤在多能性方面的差异。
